Over one-third of all strokes are cryptogenic; their cause is unknown despite testing. The prevalence of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is ~50%, yet only 25% in the general population. This suggests that paradoxical embolism (PE), venous emboli that access the arterial circulation via a PFO, is a major cause of CS. Many doctors advise PFO closure, especially for young patients, but the procedure's benefit is unproven. For someone with CS and PFO, it is not clear for that person if the PFO is causally related to the stroke or incidental, and stroke recurrence is uncommon in patients with CS and PFO (average annualized risk across studies is ~2%). While the risk is above average for some (e.g. those with atrial septal aneurysm), it must also be below average in others. How to determine that the stroke was caused by PE and how to predict recurrence risk for individuals is not known. Prior studies have been limited by extremely low statistical power for examining factors related to recurrence and have contradictory and even paradoxical findings, likely due to confounding stroke risk from other causes, which were not properly controlled for. In order to advise patients about the potential benefits of therapy, needed is a means of predicting, in the individual patient, the likelihood that the PFO was causal rather than incidental to the index event and the probability that such an event will recur. The goals of the Risk of Paradoxical Embolism (ROPE) Study are to identify: 1) patients at high risk for recurrent stroke from PE (not just recurrent stroke in general) who can be helped with PFO closure, and 2) patients who are at low risk of recurrence of PE (incidental PFO or benign natural history) who are unlikely to benefit from closure. We hypothesize that patient characteristics in those with CS (with and without PFO) can be used to identify those in whom a discovered PFO is more or less likely to be causally related to the stroke. Further, we hypothesize that, in patients with CS and PFO, the risk of stroke recurrence, and specifically recurrence from PE, is predictable from clinical, radiologic and echocardiographic variables available at the time of the index stroke. Thus, the specific aims of the ROPE Study are: 1) To build the largest database of CS using existing cohort studies of patients with CS studied with TEE, both with and without PFO, sufficiently robust to support predictive risk modeling; 2. To identify, CS patients, patient characteristics that are associated with the presence (versus the absence) of a PFO; 3) To develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics; 4) To develop an index based on these models that can stratify patients with CS and PFO by their conditional probability that the PFO was causally-related to the index stroke and the risk of stroke recurrence; 5) To apply this score to stratify patients in clinical trials testing endovascular PFO closure against medical therapy, from low-expected-benefit to high-expected-benefit, and to test for a treatment-effect-by-strata interaction. PUBLIC HEALTH RELEVANCE One out of every four people in the general population have a small hole in their heart known as a patent foramen ovale (PFO) but in patients with stroke, many of whom are young and with no explanation for why they should have had a stroke, these holes are found in around one in two people. In these patients, no one knows how to tell if the PFO allowed a blood clot to pass through it and cause a stroke or if it is an innocent bystander and the stroke was caused by something else and many doctors argue that all such holes should be closed, using new non-surgical methods, rather than just blood thinning pills. By examining the largest collection of patients ever assembled for this problem, the ROPE Study team aims to identify the patients who should have their PFO closed in order to prevent another stroke and equally importantly to identify those for whom PFO-closure would not be likely to help and may even lead to harm.